The present invention relates to a process for the preparation of baccatin III and 10-desacetylbaccatin III analogs having new C2 and/or C4 functional groups.
Taxol is a natural product extracted from the bark of yew trees. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is currently undergoing clinical trials against ovarian, breast and other types of cancer in the United States and France and preliminary results have confirmed it as a most promising chemotherapeutic agent. The structure of taxol and the numbering system conventionally used is shown below; this numbering system is also applicable to compounds used in the process of the present invention. 
In Colin U.S. Pat. No. 4,814,470, it was reported that a taxol derivative, commonly referred to as taxotere, has an activity significantly greater than taxol. Taxotere has the following structure: 
Taxol, taxotere and other biologically active tetracyclic taxanes may be prepared semisynthetically from baccatin III and 10-desacetyl baccatin III as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012 or by the reaction of a xcex2-lactam and a suitably protected baccatin III or 10-desacetylbaccatin III (xe2x80x9c10-DABxe2x80x9d) derivative as set forth in U.S. Pat. No. 5,175,315 or copending U.S. patent application Ser. No. 07/949,107 (which is incorporated herein by reference). Baccatin III 1 and 10-DAB 2 can be separated from mixtures extracted from natural sources such as the needles, stems, bark or heartwood of numerous Taxus species and have the following structures. 
The tetracyclic core of taxol and taxotere bear six singly bonded oxygen substituents. Two of these (three in the case of taxotere) are present as hydroxyl groups, and the others-are esters of three different carboxylic acids. Selective manipulation of these groups presents a formidable problem which must be overcome before a series of taxol analogs can be prepared by a rational synthetic sequence. Hydrolytic and solvolytic methods have previously encountered complications. For example, it has been reported by that hydrolysis of taxol under mildly basic conditions yields a complex mixture of products. Miller et al., J. Org. Chem. 1981, 46, 1469. Recently it has been found that solvolysis of baccatin (III) derivatives leads to rearrangement of the tetracyclic core. Farina, et al., Tetrahedron Lett. 1992, 33, 3979.
Among the objects of the present invention, therefore, is the provision of a process for selectively attaching different functional groups to the C2 and/or C4 oxygens of baccatin III and analogs or derivatives thereof; the provision of such a process which is relatively straightforward; the provision of such a process in which the C2 benzoate substituent of baccatin III and analogs or derivatives thereof may be selectively reduced or hydrolyzed and the provision of such a process in which the C4 acetate substituent may be selectively reduced.
Briefly, therefore, the present invention is directed to a process for the preparation of analogs or derivatives of baccatin III or 10-desacetyl baccatin III in which the C2 substituent and/or the C4 acetate substituent of baccatin III or 10-desacetoxy baccatin III or an analog thereof is selectively converted to the corresponding hydroxy group(s).
The present invention is additionally directed to a derivative of baccatin III or 10-desacetyl baccatin III having the formula 
wherein R4a, R7a, R10a, and R13a are as defined elsewhere herein.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
As used herein xe2x80x9cArxe2x80x9d means aryl; xe2x80x9cPhxe2x80x9d means phenyl; xe2x80x9cMexe2x80x9d means methyl; xe2x80x9cEtxe2x80x9d means ethyl; xe2x80x9ciPrxe2x80x9d means isopropyl; xe2x80x9ctBuxe2x80x9d and xe2x80x9ct-Buxe2x80x9d means tert-butyl; xe2x80x9cRxe2x80x9d means lower alkyl unless otherwise defined; xe2x80x9cAcxe2x80x9d means acetyl; xe2x80x9cpyxe2x80x9d means pyridine; xe2x80x9cTESxe2x80x9d means triethylsilyl; xe2x80x9cTMSxe2x80x9d means trimethyl-silyl; xe2x80x9cTBSxe2x80x9d means Me2t-BuSixe2x80x94; xe2x80x9cTfxe2x80x9d means xe2x80x94SO2CF3; xe2x80x9cBMDAxe2x80x9d means BrMgNiPr2; xe2x80x9cSwernxe2x80x9d means (COCl)2, Et3N; xe2x80x9cLTMPxe2x80x9d means lithium tetramethylpiperidide; xe2x80x9cMOPxe2x80x9d means 2-methoxy-2-propyl; xe2x80x9cBOMxe2x80x9d means benzyloxymethyl; xe2x80x9cLDAxe2x80x9d means lithium diisopropylamide; xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride; xe2x80x9cRed-Alxe2x80x9d means sodium bis(2-methoxyethoxy) aluminum hydride; xe2x80x9cMsxe2x80x9d means CH3SO2xe2x80x94; xe2x80x9cTASFxe2x80x9d means tris(diethylamino)sulfoniumdifluorotrimethylsilicate; xe2x80x9cTsxe2x80x9d means toluenesulfonyl; xe2x80x9cTBAFxe2x80x9d means tetrabutyl ammonium hydride; xe2x80x9cTPAPxe2x80x9d means tetrapropyl-ammonium perruthenate; xe2x80x9cDBUxe2x80x9d means diazabicycloundecane; xe2x80x9cDMAPxe2x80x9d means p-dimethylamino pyridine; xe2x80x9cLHMDSxe2x80x9d means lithium hexamethyldisilazide; xe2x80x9cDMFxe2x80x9d means dimethylformamide; xe2x80x9cAIBNxe2x80x9d means azo-(bis)isobutyronitrile; xe2x80x9c10-DABxe2x80x9d means l0-desacetylbaccatin III; xe2x80x9cFARxe2x80x9d means 2-chloro-1,1,2-trifluorotriethylamine; xe2x80x9cmCPBAxe2x80x9d means metachloroperbenzoic acid; xe2x80x9cDDQxe2x80x9d means dicyanodichloroquinone; xe2x80x9csulfhydryl protecting groupxe2x80x9d includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; xe2x80x9camine protecting groupxe2x80x9d includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; xe2x80x9cprotected hydroxyxe2x80x9d means xe2x80x94OP wherein P is a hydroxy protecting group; and xe2x80x9chydroxy protecting groupxe2x80x9d includes, but is not limited to, acetals having two to ten carbons, ketals having two to ten carbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-tri-chloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1-6 alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They maybe hetero-substituted with the various substituents defined herein, including alkaryl.
The alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. They may be heterosubstituted with the various substituents defined herein, including alkenaryl.
The alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They may be heterosubstituted with the various substituents defined herein, including alkynaryl.
The aryl moieties described herein contain from 6 to 15 carbon atoms and include phenyl. They may be hydro-carbon or heterosubstituted with the various substituents defined hereinbelow. Phenyl is the more preferred aryl.
The heteroaryl moieties described herein contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like. They may be hydrocarbon or heterosubstituted with the various substituents defined hereinbelow.
The acyl moieties described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
The alkoxycarbonyloxy moieties described herein comprise lower alkyl, alkenyl, alkynyl or aryl groups.
The hydrocarbon substituents described herein may be alkyl, alkenyl, alkynyl, or aryl, and the heterosubstituents of the heterosubstituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties described herein contain nitrogen, oxygen, sulfur, halogens and/or one to six carbons, and include lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, and nitro, heteroaryl such as furyl or thienyl, alkanoxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, and amido.
Surprisingly, it has been discovered that the C2 ester of a suitably protected derivative of baccatin III or 10-DAB having the formula 
may be selectively reduced to form a 1,2 diol having the formula 
which, in turn, may be converted to a 1,2 carbonate intermediate which permits the selective formation of a variety of C2 esters through reaction with alkyl, alkenyl, alkynyl or aryl lithium reagents or Grignard reagents. The 1,2 carbonate intermediate has the formula 
wherein
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, or xe2x80x94OCOR30;
R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo,
R7a is hydrogen, halogen, protected hydroxy, xe2x80x94OR28, or together with R7 forms an oxo;
R9 is hydrogen or together with R9a forms an oxo,
R9a is hydrogen, hydroxy, protected hydroxy, or together with R9 forms an oxo;
R10 is hydrogen or together with R10a forms an oxo,
R10a is hydrogen, hydroxy, protected hydroxy, or together with R10 forms an oxo;
R13 is hydroxy or protected hydroxy;
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R28 is hydrogen, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative; and
R30 and R31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl.
Any agent which selectively removes the C2 and/or C4 acyl groups and thereby converts the ester(s) to the corresponding alcohol(s) may be used. The agent may be a reducing agent, preferably a hydride of aluminum or boron, more preferably an alkyl substituted aluminum hydride or an alkyl substituted borohydride, and most preferably lithium aluminum hydride (xe2x80x9cLAHxe2x80x9d), sodium bis(2-methoxyethoxy) aluminum hydride (xe2x80x9cRed-Alxe2x80x9d) or lithiumtriethylborohydride. Alternatively, the agent may be a base, preferably a tetraalkylammonium base and most preferably, tetrabutylammoniumhydroxide. The conversion of the ester to the corresponding alcohol is carried out in a single phase, non-aqueous system such as methylene chloride.
After the C2 and/or C4 esters are reduced to the corresponding alcohol(s), standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine can be used to form new esters at C2 and/or C4. Alternatively, the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
As will be discussed in greater detail below, baccatin III and 10-DAB derivatives having new C2 and/or C4 esters can be produced by several reaction schemes. To simplify the description, 10-DAB is used as the starting material in Reaction Schemes 1-6. Baccatin III derivatives or analogs, however, may be produced using the same reactions (except for the protection of the C10 hydroxy group with TES) by simply replacing 10-DAB with baccatin III as the starting material. 
In Reaction Scheme 1, the C7 hydroxyl group of 10-deacetyl baccatin (III) was selectively protected as its triethylsilyl (TES) ether as described by Green, et al., JACS 110, 5917 (1988). The C10 hydroxyl group was then protected as the TES ether through the use of n-butyllithium and triethylsilyl chloride. The C13 hydroxyl group was subsequently protected as the trimethylsilyl (TMS) ether, which could be selectively removed at a later stage. The fully protected 13-O-trimethylsilyl-7,10-bis-O-triethylsilyl10-deacetyl baccatin (III) 3 underwent selective reduction with Red-Al to give the 2 hydroxy derivative 4. 2 hydroxy derivative 4 may alternatively be obtained by selectively reducing the fully protected baccatin III 3 with tetrabutylammonium borohydride in either or by hydrolyzing the C4 ester of fully protected baccatin III with tetrabutylammoniumhydroxide. Deprotonation of 4 with ether n-butyllithium or a bulky amide base such as LDA was followed by the addition of an appropriate acid chloride to provide the C2 ester derivative 5. The C13 TMS group may then be removed using HF.
As shown in Reaction Scheme 2, 1,2 diol 4 can be readily converted to the 1,2 carbonate 6 which can be transformed to the C2 formate 5 (R31=H) by treatment with Red-Al under mild conditions. In addition, carbonate 6 reacts selectively with nucleophilic agents (e.g., Grignard reagents or alkyllithium reagents) to provide the C2 ester derivative 5. Again, the C13 TMS group may then be removed using HF. 
10-DAB analogs having different substituents only at C4, or at both C2 and C4 can be prepared as set forth in Reaction Schemes 3-6.
In Reaction Scheme 3, protected 10-DAB 3 is converted to the triol 7 with lithium aluminum hydride. Triol 7 is then converted to the corresponding C2 ester using Cl2CO in pyridine followed by a nucleophilic agent (e.g., Grignard reagents or alkyllithium reagents). 
Alternatively, protected 10-DAB 3 may be converted directly to the C2 ester by treating 10-DAB 3 with lithiumtriethylborohydride which selectively cleaves the C4 acetyl group. Also, deprotonation of triol 7 with LDA followed by introduction of an acid chloride selectively gives the C4 ester. For example, when acetyl chloride was used, triol 7 was converted to 1,2 diol 4 as set forth in Reaction Scheme 4. 
Triol 7 can also readily be converted to the 1,2 carbonate 8. Acetylation of carbonate 8 under vigorous standard conditions provides carbonate 6 as described in Reaction Scheme 5; addition of alkyllithiums or Grignard reagents to carbonate 6 provides the C2 ester having a free hydroxyl group at C4 as set forth in Reaction Scheme 2. As set forth in Reaction Scheme 6, other C4 substituents can be provided by reacting carbonate 8 with an acid chloride and a tertiary amine to yield carbonate 10 which is then reacted with alkyllithiums or Grignard reagents to provide 10-DAB derivatives having new substituents at C2 as set forth in Reaction Scheme 6. 
Taxanes having alternative acyloxy C2 and C10 substituents may be prepared as set forth in Reaction Scheme 7, using, for example, baccatin III as a starting material. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 12. Tetraol 12 is converted to carbonate 13 using Cl2CO and pyridine, and carbonate 13 is acylated at C10 with an acid chloride and pyridine to produce carbonate 14 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 14 under vigorous standard conditions provides carbonate 15 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10. 
10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB having alternative C2 and C4 substituents may be produced using the same reactions (except for the protection of the C10 hydroxy group with TES) by simply replacing 10-DAB with 10-desacetoxy baccatin III as the starting material in Reaction Schemes 1-6. Baccatin III and 10-DAB may be selectively and nearly quantitatively converted to the corresponding 10-desacetoxy or 10-desoxytaxane when they are reacted with samarium diiodide. Alternatively, the 10-DAB derivatives having alternative C2 and C4 substituents may themselves be reacted with samarium diiodide to yield the corresponding 10-deacetoxy compound.
As illustrated in Reaction Scheme 8, the reaction of baccatin III with Bu4NBH4 in methylene chloride yields 9-desoxo-9xcex2-hydroxybaccatin III 5. After the C7 hydroxy group is protected with the triethylsilyl protecting group, for example 7-protected-9xcex2-hydroxy derivative 6 may be used as a starting material in Reaction Schemes 1-7. 
Alternatively, the C13 hydroxy group of 7-protected-9xcex2-hydroxy derivative 6 may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 9, to enable further selective manipulation of the various substituents of the taxane. For example, reaction of 7,13-protected-9xcex2-hydroxy derivative 7 with KH causes the acetate group to migrate from C10 to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8. Protection of the C10 hydroxy group of 10-desacetyl derivative 8 with triethylsilyl yields derivative 9. Selective removal of the C13 hydroxy protecting group from derivative 9 yields derivative 10 which may be used as a starting material in Reaction Schemes 1-7. 
As shown in Reaction Scheme 10, 10-oxo derivative 11 can be provided by oxidation of 10-desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxanes having a C13 side chain. Alternatively, the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 which can be used as a starting material for Reaction Schemes 1-7. 
Reaction Scheme 11 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13. The C7 and C10 hydroxyl groups of pentaol 13 can then be selectively protected with the triethylsilyl or another protecting group to produce triol 14 which a can be used as a starting material for Reaction Schemes 1-7 above. 
Taxanes having C9 and/or C10 ayloxy substituents other than acetate can be prepared using 10-DAB as a starting material as illustrated in Reaction Scheme 12. Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of 7-protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent. Selective reduction of the C9 keto substituent of derivative 16 yields 9B-hydroxy derivative 17 to which a C13 side chain may be attached. Alternatively, the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 9, above. 
10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium diiodide. Reaction between the tetracyclic taxane having a C10 leaving group and samarium diiodide may be carried out at 0xc2x0 C. in a solvent such as tetrahydrofuran. Advantageously, the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed. Thereafter, the C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9xcex2-hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 13, 14 and 14a. 
As shown in Reaction Scheme 14, Baccatin III may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution. Other baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride.
Taxanes having C7 acyloxy substituents can be prepared as set forth in Reaction Scheme 14a, 7,13-protected 10-oxo-derivative 11 is converted to its corresponding C13 alkoxide by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a xcex2-lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
A wide variety of tricyclic taxanes are naturally occurring, and through manipulations analogous to those described herein, an appropriate side chain can be attached to the C13 oxygen of these substances. Alternatively, as shown in Reaction Scheme 15, 7-O-triethylsilyl baccatin III can be converted to a tricyclic taxane through the action of trimethyloxonium tetrafluoroborate in methylene chloride solution. The product diol then reacts with lead tetraacetate to provide the corresponding C4 ketone. 
Recently a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) has been discovered in an extract of yew needles (CandEN, p 36-37, Apr. 12, 1993). Derivatives of this hydroxylated taxane having the various C2, C4, etc. functional groups described above may also be prepared by using this hydroxylated taxane. In addition, the C14 hydroxy group together with the C1 hydroxy group of 10-DAB can be converted to a 1,2-carbonate as described in CandEN or it may be converted to a variety of esters or other functional groups as otherwise described herein in connection with the C2, C4, C7, C9, C10 and C13 substituents.
Synthesis of tetracyclic taxanes having a C13 side-chain and different substituents at C2 and/or C4 can readily be prepared from baccatin III and 10-DAB derivatives having different substituents at C2 and/or C4 using presently known methods. For instance, a suitable side chain may be attached to a baccatin III or 10-DAB derivative as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012 or by the reaction of a xcex2-lactam and a suitably protected baccatin III or 10-desacetylbaccatin III derivative as illustrated in Reaction Scheme 14a wherein X1-X5 are as follows:
X1 is xe2x80x94OX6, xe2x80x94SX7, or xe2x80x94NX8X9;
X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 and X4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X5 is xe2x80x94COX10, xe2x80x94COOX10, xe2x80x94COSX10, xe2x80x94CONX8X10, or xe2x80x94SO2X11;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X9 is an amino protecting group;
X10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, xe2x80x94OX10, or xe2x80x94NX8X14; and
X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.